Diabetes is sub-divided on clinical grounds into insulin-dependent and non-insulin dependent diabetes mellitus (IDDM (type 1) and NIDDM (type 2) respectively). The two forms of the disease are distinguished by a number of features.
In type 1 diabetes there is profound insulin deficiency such that even the low levels of insulin which would normally prevent lipolysis and cytogenesis cannot be sustained. Type 1 patients therefore generally show high levels of glucose and low levels of insulin. As the disease progresses, the pancreatic islets are damaged or destroyed, and less and less insulin can be produced.
Type 2 diabetes is a common and complex disorder, which results from a combination of defects in insulin secretion and impaired insulin sensitivity (insulin resistance) in peripheral tissues, e.g. in skeletal muscle (1). Type 2 diabetes is characterized by hyperglycaemia in both the fasted and fed states, variable degrees of hyperinsulinaemia and obesity. Despite intensive investigation of proteins in insulin signaling pathways in the past decade, the primary cellular cause remains uncertain. Recent reports of reduced oxidative enzyme activity in type 2 diabetic muscle (2), and of mitochondrial DNA mutations causing type 2 diabetes through impairment of oxidative phosphorylation (3,4), add to the molecular complexity of this disease.
Current therapy includes diet, sulphonylurea to enhance insulin secretion, insulin itself, and biguanides to reduce insulin resistance. There is a need for new antidiabetic agents, since biguanides are quite toxic while sulphonylurea is ineffective in patients with severely impaired islet cell function, and after 10 years of treatment, 50% of patients will have become resistant.
A number of strategies have been employed in order to determining the predisposition of diabetes. In WO 00/66762, to which reference is made, it is described that specific mutations in the mitochondrial gene ATP synthase 8/6 sequence can be related to diabetes.
Further, WO 00/66782 and WO 98/17826 describe a method for diagnosing diabetes by finding mutations in an ATP synthase gene.
Though several strategies for determining the risk of developing diabetes have been suggested, no strategy has proven successful. The present invention therefore fulfils the long-felt need for a method for determining the risk of developing diabetes.